Inflammatory bowel diseases
Autophagy related gene IRGM1 has been linked to Crohn's disease by genome-wide association studies. Deletion polymorphism upstream of IRGM1 was associated with the down-regulation of IRGM1 expression in patients with Crohn's disease. However, it is still largely unknown how IRGM1 may contribute to Crohn's disease progression. Growing evidence have suggested that neutrophils are actively involved in Crohn's disease activities. Autophagy is important for the function of neutrophil. Here, we investigated the potential role of IRGM1 mediated neutrophil autophagy in inflammatory bowel disease using DSS-induced colitis mice model. We showed that IRGM1 was strongly upregulated in the tissue infiltrated neutrophils after DSS administration. In addition, IRGM1 knock-out (KO) mice developed more severe disease phenotype as indicated by both greater body weight loss and tissue damage. More importantly, the injection of IRGM1 KO neutrophils to the neutrophil deficient mice copied the phenotype of IRGM1 pan KO mice indicating the important role of neutrophil IRGM1 during disease progression. Furthermore, we demonstrated both in vitro and in vivo that IRGM1 deficient neutrophils showed a decrease of autophagy activity. These data together suggested that IRGM1 mediated neutrophil autophagy maybe important for the pathogenesis of Crohn's diseases and provide a potential novel therapeutic target.